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Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus,persisters and biofilms

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Bioactive Materials 2022年第8期7卷 272-289页

作者： Shutao Zhang Xinhua Qu Juyang Jiao Haozheng Tang Minqi Wang You Wang Hongtao Yang Weien Yuan Bing Yue Department of Bone and Joint Surgery Department of OrthopedicsRenji HospitalShanghai Jiaotong University School of MedicineChina School of Medical Science and Engineering Beihang UniversityBeijing100191China Engineering Research Center of Cell&Therapeutic Antibody Ministry of EducationSchool of PharmacyShanghai Jiao Tong UniversityShanghai200240China

Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.

关键词： Aminoglycosides Felodipine persisters Methicillin-resistant Staphylococcus aureus Implant infection

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Drug resistance in glioblastoma:are persisters the key to therapy

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Cancer Drug Resistance 2020年第3期3卷 287-301页

作者： Lisa Oliver Lisenn Lalier Céline Salaud Dominique Heymann Pierre François Cartron François M.Zallette Universitéde Nantes INSERMCRCINANantes 44007France. CHU de Nantes Nantes 44093France. LaBCT ICOSaint Herblain 44805France.

Glioblastoma(GBM)represents the main form of brain tumors in adults,and one of the most aggressive cancers overall.The treatment of GBM is a combination of surgery(when possible),chemotherapy(usually Temozolomide,TMZ)and radiotherapy(RT).However,despite this heavy treatment,GBM invariably recur and the median length of survival following diagnosis is 12 to 15 months,with less than 10%of people surviving longer than five years.GBM is extremely resistant to most treatments because of its heterogeneous nature,which is associated with extreme clonal plasticity and the presence of cancer stem cells,refractory to TMZ-and RT-induced cell death.In this review,we explore the mechanisms by which cancer cells,and especially GBM,can acquire resistance to treatment.We describe and discuss the concept of persister/tolerant cells that precede and/or accompany the acquisition of resistance.Persister/tolerant cells are cancer cells that are not eliminated by treatment(s)because of different mechanisms ranging from dormancy/quiescence to senescence.We discuss the possibility of targeting these mechanisms in new therapeutic regimen.

关键词： Drug resistance persisters tolerance chromatin remodeling metabolism tumor environment

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Identification of Persister Drug Combination Clinafloxacin+Cefuroxime+Gentamicin That Eradicates Persistent Pseudomonas aeruginosa Infection in a Murine Cystic Fibrosis Model

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Infectious Microbes & Diseases 2023年第1期5卷 21-28页

作者： Yuting Yuan Rebecca Yee Naina Gour Xinzhong Dong Jie Feng Wanliang Shi Ying Zhang Department of Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA The Solomon H.Snyder Department of Neuroscience and the Center for Sensory Biology Johns Hopkins University School of MedicineBaltimoreMarylandUSA State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Research Units of Infectious Disease and Microecology Chinese Academy of Medical SciencesHangzhouZhejiangChina Jinan Microecological Biomedicine Shandong Laboratory JinanShandongChina

Pseudomonas aeruginosa can cause persistent infections,such as biofilm infections,in cystic fibrosis patients,which are difficult to cure due to non-growing persister bacteria that are not effectively killed by the current treatments.While antibiotic activity against growing P.aeruginosa is well documented,their activity against non-growing stationary phase cultures is less clear.Here,we evaluated six major classes of antibiotics,including cell wall and cell membrane inhibitors,protein synthesis inhibitors,DNA synthesis inhibitors,RNA synthesis inhibitors,sulfa drugs and nitrofurantoin,for their activity against growing and non-growing P.aeruginosa.We foundthat cell wall and cell membrane inhibitors(cefuroxime and colistin),DNA synthesis inhibitors(clinafloxacin)and sulfa drugs(sulfamethoxazole)had good activity against stationary-phase bacteria,while protein synthesis inhibitors(gentamicin),RNA synthesis inhibitor(rifampin)and nitrofurantoin showed relatively poor activity.Clinafloxacin was the only drug able to completely eradicate stationary-phase bacteria within four days.The cefuroxime+gentamicin+clinafloxacin combination was able to kill all bacteria from a biofilm within two days,whereas the clinically used drug combination cefuroxime+gentamicin/colistin only partially killed the biofilmbacteria.In amurine persistent cystic fibrosis lung infectionmodel,only the cefuroxime+gentamicin+clinafloxacin drug combination eradicated all bacteria from the lungs,whereas clinafloxacin alone,cefuroxime+clinafloxacin or the currently recommended drug combination cefuroxime+gentamicin failed to do so.The complete eradication is a property of the clinafloxacin combination,as the otherwise identical levofloxacin combination did not clear the bacterial loads from the lungs.Our findings offer new therapeutic options for more effective treatment of persistent P.aeruginosa infections,with possible implications for treating other persistent infections.

关键词： Pseudomonas aeruginosa persisters stationary-phase bacteria biofilm clinafloxacin cystic fibrosis

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Botanical Medicines With Activity Against Stationary Phase Bartonella henselae

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Infectious Microbes & Diseases 2021年第3期3卷 158-167页

作者： Xiao Ma Jacob Leone Sunjya Schweig Ying Zhang Department of Molecular Microbiology and Immunology Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreMarylandUSA FOCUS Health Group NaturopathicNovatoCaliforniaUSA California Center for Functional Medicine KensingtonCaliforniaUSA State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina

Bartonella henselae is a Gram-negative bacterium and is the causative agent of cat scratch disease.In humans,infections with B.henselae can result in acute or chronic systemic infections with diverse clinical symptoms.The current treatment for Bartonella infections with antibiotics such as doxycycline and rifampin is not always effective,presumably due in part to bacterial persistence.There are various anecdotal reports of herbal extracts used for treating patients with persistent Bartonella infections but their activity on B.henselae is unknown.In order to identify more effective therapies for persistent Bartonella infections,in this study,we tested the antimicrobial activity of botanical and herbal medicines and screened an herbal product collection against stationary phase B.henselae in vitro using a SYBR Green I/propidium iodide viability assay.We identified five herbal product extracts(at 1.67 mg/mL or 2.5mg/mL),including Cryptolepis sanguinolenta,Juglans nigra,Polygonum cuspidatum,Scutellaria baicalensis,and Scutellaria barbata,that had high activity against stationary phase B.henselae.Among them,C.sanguinolenta,J.nigra,and P.cuspidatum could eradicate all stationary phase B.henselae cells within 7days at 0.83 mg/mL or 1.25 mg/mL in drug exposure time-kill assays,whereas S.baicalensis and S.barbata showed relatively poor activity.These top hits were active against both stationary phase nongrowing B.henselae and log phase growing B.henselae in minimum inhibitory concentration testing.These findings may have implications for improved treatment of persistent Bartonella infections.

关键词： antimicrobial activity Bartonella henselae botanical medicine herbal medicine medicinal plant persisters phytotherapy stationary phase

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